The present invention relates to the use of xcex1-alkylglucosides and/or xcex1-alkylglucoside esters, more particularly to xcex1-butylglucoside esters, as an antimicrobial agent, in particular an antibacterial and/or antifungal agent, in the preparation of pharmaceutical, cosmetic or agro-alimentary compositions, or other types of compositions when such an antimicrobial agent needs to be present. The invention also relates to specific compositions for such uses which comprise such antimicrobial agents.
Protecting cosmetic, dermatological, pharmaceutical and agro-alimentary products against possible microbial development necessitates the use of preservatives. However, the majority of preservatives in current use, in particular in cosmetics and in topical patent medicines, tend to cause skin and eye irritation. Further, they may be incompatible with the components used, in particular some surfactants.
Sugar or alkylglucoside fatty acid esters are known for their emulsifying and conditioning properties for the hair and for skin. Their use in cosmetics has been described in a number of articles and patent applications.
The inventors have unexpectedly discovered that xcex1-alkylglucoside esters have bactericidal and/or fungicidal properties in addition to their known emulsifying properties. In parallel, it has been discovered that xcex1-alkylglucosides, some of which could constitute the substrate for the esterification reaction providing said esters, also have certain antimicrobial properties, in particular bactericidal properties.
One aim of the present invention is thus to provide means for effectively preventing or reducing microbial development in a medium which is suitable therefor, while avoiding the problems inherent in using some types of preservatives as mentioned above.
In a first aspect, then, the invention concerns the use in a composition, in particular in a pharmaceutical, cosmetic or agro-alimentary composition, of an xcex1-alkylglucoside component or an xcex1-alkylglucoside ester component or a mixture thereof, as a microbicidal agent, in particular a bactericide or fungicide or both at the same time, said component or said mixture being in a proportion which is sufficient to preserve said composition from microbial development, in particular bacterial or fungal development, or both at the same time.
Clearly, the present invention also encompasses the use of mixtures of at least two different xcex1-alkylglucoside ester and/or xcex1-alkylglucoside components.
The preserving property of such compounds thus provides a xe2x80x9cself-protectingxe2x80x9d effect against microbial contamination of pharmaceutical, cosmetic, dermatological or agro-alimentary formulations. xcex1-alkylglucoside esters, in particular xcex1-butylglucoside esters, can be obtained by enzymatic esterification using an xcex1-alkylglucoside such as that described in International patent PCT/FR92/00782. The products obtained by that process are stereospecific (xcex1) and are normally monoglucosides. Because of the absence of xcex2 anomer in the products used in the present invention, certain physical characteristics, such as the melting point and the solubility of the alkylglucoside, are defined very precisely.
xcex1-alkylglucosides are preferably esterified in the C6 then the C2 position. This enzymatic esterification is catalysed by enzymatic preparation with a lipase activity. The reaction conditions can either enrich the proportion of xcex1-alkylglucoside monoester, mainly with esterification at C6, or enrich the proportion of diester, with esterification mainly at C2 and C6. The process can esterify both saturated fatty acids and unsaturated fatty acids.
Such esters are stereospecific, chemically pure and completely characterized. They are also not mixed with secondary products, provided that they are obtained by an entirely enzymatic synthesis process. Since these xcex1-alkylglucoside esters are also non toxic and non irritating emulsifying agents, they are particularly suitable for cosmetic, pharmaceutical or alimentary use.
The xcex1-alkylglucoside ester component, xcex1-alkylglucoside component or mixture thereof is preferably in a proportion in the range from about 0.5% to 10%, preferably in the range about 2.5% to 5% by weight of said composition.
Further, when acting as a bactericidal agent, the xcex1-alkylglucoside ester component is in a proportion of at least about 3.5%, preferably 5%, by weight of the composition.
The alkyl group of the xcex1-alkylglucoside or the xcex1-alkylglucoside ester is preferably a group containing 1 to 6 carbon atoms, preferably a butyl group.
The xcex1-butylglucoside ester preferably represents at least 40%, preferably 80%, by weight of bactericidal and/or fungicidal agent.
Particularly preferably, the xcex1-alkylglucoside ester is an xcex1-butylglucoside mono- or di-caprate, an xcex1-butylglucoside mono- or di-palmitate, or an xcex1-butylglucoside mono- or di-cocoate.
Laurates, myristates and stearates are esters which can also be used.
As described above, the inventors have also discovered the bactericidal and fungicidal properties of xcex1-alkylglucosides. In a preferred use of the present invention, when used as a bactericidal agent, the xcex1-alkylglucoside component is in a proportion in the range about 0.8% to 5% by weight of the composition, and when used as a fungicidal agent, it is in a proportion in the range about 1% to 3% by weight of the composition.
The microbicidal activity of the above components may vary to a certain extent depending on the conditions of use. The skilled person is clearly at liberty to adapt these conditions to obtain the desired microbicidal effect.
The present invention also relates to a pharmaceutical, cosmetic or agro-alimentary composition the active principle of which comprises an xcex1-alkylglucoside ester, an xcex1-alkylglucoside or a mixture thereof, the alkyl group of which contains 1 to 6 carbon atoms. Preferably, this active principle is present in an amount of 0.5% to 10%, preferably 2.5% to 5%, by weight with respect to said composition.
Preferably, the alkyl group of the xcex1-alkylglucoside and/or xcex1-alkylglucoside ester is a group containing 1 to 6 carbon atoms, preferably a butyl group.
In a preferred composition of the invention, the xcex1-alkylglucoside ester is an xcex1-butylglucoside mono- or di-caprate, an xcex1-butylglucoside mono- or di-palmitate, or an xcex1-butylglucoside mono- or di-cocoate.
In a particularly preferred composition, the active principle is constituted by one of the following mixtures a), b), c) or d):
These mixtures a), b), c) and d) are respectively termed: BEC 4, BEC 721985, BEC SCS and BEC SH.
Preferably again, the pH of the composition of the invention is in the range 3 to 10, and preferably about 5.
The present invention also relates to a process for preparing an xcex1-alkylglucoside ester for use in accordance with the invention, in which said xcex1-alkylglucoside ester is obtained by stereospecific enzymatic esterification of xcex1-butylglucoside in the presence of a thinning agent, in particular hexane.
The present invention also relates to a process for external antimicrobial treatment, in particular in man, in which the xcex1-alkylglucoside and xcex1-alkylglucoside ester type compounds described above act as anti-bactericidal and/or antifungal agents, in different galenical forms.
The inventors thus tested the bactericidal and/or fungicidal activity of xcex1-alkylglucoside and xcex1-alkylglucoside ester type compounds to determine the conditions, in particular the concentrations, under which said compounds have to be used for the desired activities to be obtained. The results of these tests were analysed in accordance with the xe2x80x9cPharmacopxc3xa9e Franxc3xa7caisexe2x80x9d which describes a methodology for monitoring the efficacy of antimicrobial preservation agents in pharmaceutical preparations and establishes minimum efficacy criteria as a function of the administration routes of a medicine. Thus specific criteria are fixed for topical patent medicines which can be considered to be close to cosmetic products in their conception. The recommended and significant criteria for bactericidal and/or fungicidal activity of a product are:
for a bactericidal effect (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli):
reduction of 3 logarithmic units in 14 days with respect to the initial population;
no increase in microbial growth after 14 days and up to the 28th day, when the test is stopped;
for a fungicidal effect (yeasts and moulds) (Candida albicans, Aspergillus niger):
reduction of one logarithmic unit in 14 days with respect to the initial population;
no increase in microbial growth after 14 days and up to the 28th day, when the test is stopped.
In order to facilitate visualisation of the bactericidal or fungicidal effect of the tested compounds, the results obtained were transcribed into the graphical forms of FIG. 5 which show the reduction in the number of germs in logarithmic units, over time (1 day, 7 days, 14 days, 21 days, 28 days).